DESCRIPTION (Applicant's abstract): Many, if not most, central nervous system disorders show clinical variability between patients. Even in inherited disorders where a cohort of patients can share the same genetic and biochemical lesion, patients will show clinically discordant phenotypes. Here, we propose to investigate the molecular basis for clinical variability with identical genetic lesions and genetic backgrounds using expression profiling of mouse spasticity models. Spasticity is a common neurological symptom that can reflect damage to the brain or spinal cord, or can reflect any one of a series of inbred biochemical defects. Mouse models of inherited spasticity fall into two recessive linkage groups. One group is due to loss-of-function mutations of the alpha 1 subunit of the inhibitory glycine receptor, while the second group is due to loss-of-function mutations of the beta subunit. Two alleles of these mutants, spastic and spasmodic, are particularly interesting in their progression of the disorder. Affected homozygotes show normal birth and early development, but then develop a progressive spastic phenotype by 3 to 5 weeks of age. After this time, the phenotype is variable, with some mice showing clinical improvement of the spasticity, while littermates can show significant worsening with age. This clinical variability is despite the identical mutation, in the same inbred genetic background. Our hypothesis is that critical differences in pathophysiological cascades arc occurring in clinically discordant littermates. We propose that these differences can be identified by expression profiling of spinal cords of affected mice. The identification of consistent expression changes associated with clinical worsening or clinical improvement of spasticity will identify key pathways amenable to drug modulation. We hypothesize that the drug targets identified by this expression profiling approach could prove useful in all spasticity syndromes, and possibly in improving spinal cord recovery from damage. Our laboratory at the Children's National Medical Center is fully equipped for expression profiling by both cDNA arrays, and Affymetrix technologies. We show preliminary data on expressing profiling of the spastic mouse spinal cord relative to normal controls using Affymetrix stock chips, which identify both expected, and unexpected changes. This research proposal has two aims; in the first, we will conduct Affymetrix expression profiling in a limited series of mouse spinal cords, using both spastic (alpha 1 subunit deficiency) and spasmodic (beta subunit deficiency) mice. We will then produce custom cDNA arrays of all genes showing "dif" calls, and perform a series of expression profiling experiments on discordant littermates. Comparison of the genes showing consistent dif calls in discordant littermates by the cDNA microarrays should identify important pathological cascades that play a role in dictating clinical severity. Our findings should have significance for the progression of inherited forms of spastic paraplegia but also more broadly for spinal cord injury and CNS homeostasis.